title: Activin A impairs insulin action in cardiomyocytes via up-regulation of miR-143.
abstract: OBJECTIVE
  Enhanced activin A release from epicardial adipose tissue (EAT) has been linked to the development of cardiac dysfunction in type 2 diabetes (T2D). This study examined whether the inhibition of insulin action induced by epicardial adipokines in cardiomyocytes can be ascribed to alterations in miRNA expression.
  
  
  RESULTS
  Expression levels of miRNAs were assessed by real-time PCR in primary adult rat cardiomyocytes (ARC) exposed to conditioned media generated from EAT biopsies (CM-EAT) from patients with and without T2D. CM-EAT-T2D altered the expression of eight miRNAs in ARC vs. CM-EAT from patients without T2D. Of these, only expression of the miR-143/145 cluster was affected by activin A in the same direction as CM-EAT-T2D. Accordingly, activin A neutralizing antibodies prevented the induction of the miR-143/145 cluster by CM-EAT-T2D. Subsequently, the impact of the miR-143/145 cluster on insulin action was investigated. Transfection of HL-1 cells with precursor-miR-143 (pre-miR-143), but not pre-miR-145, blunted the insulin-mediated phosphorylation of Akt and its substrate proline-rich Akt substrate of 40 kDa (PRAS40), and reduced insulin-stimulated glucose uptake. Also lentivirus-mediated expression of pre-miR-143 in ARC reduced insulin-induced Akt phosphorylation. These effects were ascribed to down-regulation of the miR-143 target and regulator of insulin action, the oxysterol-binding protein-related protein 8 (ORP8) in both ARC and HL-1 cells. Finally, LNA-anti-miR-143 protected against the detrimental effects of CM-EAT-T2D on insulin action in ARC.
  
  
  CONCLUSIONS
  Activin A released from EAT-T2D inhibits insulin action via the induction of miR-143 in cardiomyocytes. This miRNA inhibits the Akt pathway through down-regulation of the novel regulator of insulin action, ORP8.
authors.affiliation: Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Auf'm Hennekamp 65, D-40225 Duesseldorf, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Blumensatt
authors.forename: Sabrina
authors.initials: S
authors.lastname: Greulich
authors.forename: Daniella
authors.initials: D
authors.lastname: Herzfeld de Wiza
authors.forename: Heidi
authors.initials: H
authors.lastname: Mueller
authors.forename: Bujar
authors.initials: B
authors.lastname: Maxhera
authors.forename: Martijn J
authors.initials: MJ
authors.lastname: Rabelink
authors.forename: Rob C
authors.initials: RC
authors.lastname: Hoeben
authors.forename: Payam
authors.initials: P
authors.lastname: Akhyari
authors.forename: Hadi
authors.initials: H
authors.lastname: Al-Hasani
authors.forename: Johannes B
authors.initials: JB
authors.lastname: Ruige
authors.forename: D Margriet
authors.initials: DM
authors.lastname: Ouwens
mesh_terms: D028341:Activins / Q000502:physiology*; D054392:Adipokines / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D058065:Diabetic Cardiomyopathies / Q000209:etiology; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D035683:MicroRNAs / Q000032:analysis / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D054392:Adipokines; C542359:MIRN143 microRNA, human; D035683:MicroRNAs; C422405:activin A; D028341:Activins; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Activin A; Diabetic cardiomyopathy; Epicardial adipose tissue; Insulin resistance; miRNA